Multiple myeloma (MM) is an incurable disease of uncontrolled plasma cell proliferation. There are nearly 3,000 different cellular metabolic enzymes and proteins which function to support proliferation, yet at this time it is unknown how many of these are essential to the growth of a MM tumor cell. I propose to use a new genetic technique known as CRISPR to systematically silence the function of each of the 3,000 metabolic enzymes in 20 different patient-derived MM tumor cell lines and study the effect on proliferation. I will then identify metabolic genes that are essential in all MM cells as well as those that are selectively essential in certain MM cells. I will investigate the gene expression pattern and functional significance of these two lists to identify functional MM metabolic subtypes. Next, I will focus on metabolic genes that are synthetically lethal with the MM-specific chromosomal translocation t(4;14) which is associated with a poor patient prognosis. Collectively this proposal will allow us to identify metabolic enzymes that may be therapeutically inhibited for new MM treatments.